1. Field of the Invention
The present invention relates to a process for preparing N-alkylnaltrexone halides.
2. Description of the Art
N-Alkyl quaternary derivatives of naltrexone (a nomenclature of naltrexone being (5α)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one or N-cyclopropylmethylnoroxymorphone) are known for their therapeutic applications, especially N-methylnaltrexone, the use of which makes it possible to combine a morphine treatment in a patient, significantly reducing the adverse side effects of morphine and derivatives thereof, especially on the gastrointestinal tract.
The term “N-methylnaltrexone” more particularly means (R)-N-methylnaltrexone, i.e. the compound of (R) configuration relative to the nitrogen atom, it being well known to those skilled in the art that the (S)-N-methyl compound has activity opposite to that desired for accompanying a morphine-based treated.
The configuration of the quaternary ammonium of the N-methylnaltrexone having the formula below was determined by 1H NMR of the isolated (R) and (S) diastereoisomers:
                (S) configuration of the ammonium (equatorial methyl): R1 represents a methyl group and R2 represents a methylcyclopropyl group, and        (R) configuration of the ammonium (axial methyl): R2 represents a methyl group and R1 represents a methylcyclopropyl group.        
The chemical shifts in 1H NMR of the methyl group (reference TMS or tetramethylsilane) are at 3.62 ppm for the (R) configuration and at 3.13 ppm for the (S) configuration.
U.S. Pat. No. 4,176,186 (Boehringer Ingelheim GmbH) describes quaternary noroxymorphone derivatives and also processes for preparing them. However, the described processes comprise conditions, especially of super atmospheric pressure, of necessary amount of reagent, and of conversion by column anion exchange, which are incompatible with the desired industrial application.
International Patent application, WO 2004/043 964 A2 describes a process at lower pressures, comprising the use of an anhydrous solvent system, especially 1-methyl-2-pyrrolidone, but which nevertheless still has drawbacks in terms of impurities, the imperative sufficiently low content of which inevitably leads to an unsatisfactory yield.
There was thus ever-increasing interest in having available a process for the industrial-scale production of such derivatives, under the best conditions in terms of production (safety and environment) and yield.